PNNP-Catalyzed Imine

Article pubs.acs.org/Organometallics

Highly Enantioselective Ruthenium/PNNP-Catalyzed Imine Aziridination: Evidence of Carbene Transfer from a Diazoester Complex Joel̈ Egloff, Marco Ranocchiari, Amata Schira, Christoph Schotes, and Antonio Mezzetti* Department of Chemistry and Applied Biosciences, ETH Zürich, CH-8093 Zürich, Switzerland S Supporting Information *

ABSTRACT: The ruthenium/PNNP complexes [RuCl(Et2O)(PNNP)]Y (Y = PF6, 4PF6; BF4, 4BF4; or SbF6, 4SbF6) (10 mol %) catalyze the enantioselective aziridination of imines with ethyl diazoacetate (EDA) as carbene source (PNNP = (1S,2S)-N,N′-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine). The highest enantioselectivity was obtained with 4SbF6, which aziridinated Nbenzylidene-1,1-diphenylmethanamine (5a) to cis-ethyl 1benzhydryl-3-phenylaziridine-2-carboxylate (cis-6a) with 93% ee at 0 °C. To the best of our knowledge, this is the highest enantioselectivity ever obtained in transition metal-catalyzed asymmetric aziridination. Aziridine yields were overall moderate to low (up to 33% isolated yield of the cis isomer) because of the competitive formation of diethyl maleate (7). The scope of the catalyst was studied with p- and m-substituted imines. NMR spectroscopic studies with 13C- and 15N-labeled EDA indicate that aziridine 6a is formed by carbene transfer from an EDA complex, [RuCl(EDA)(PNNP)]PF6 (8), to the imine. The observation of a dinitrogen complex (9) gives further support to this mechanism. The EDA adduct 8 decomposes to the carbene complex [RuCl(CHCO2Et)(PNNP)]+ (10), whose reaction with EDA gives diethyl maleate. This unprecedented mechanism is rationalized on the basis of the nucleophilic nature of diazoalkanes, which is enhanced by coordination to a π-back-donating metal such as ruthenium(II).

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complex formed from ethyl diazoacetate (EDA) (Scheme 1a).4 He suggested that the resulting nitrogen ylide is relatively stable and can partially dissociate from the chiral catalyst before collapsing to aziridine, as indicated by the formation of pyrrolidines in the presence of dimethyl fumarate (Scheme 2). This broadly supported mechanism 5 explains the low enantioselectivity typically observed both with copper catalysts

INTRODUCTION

Chiral alkoxycarbonyl-substituted aziridines are valuable strainactivated electrophilic precursors to amino acids as they undergo ring-opening with excellent stereo- and regiocontrol.1 A straightforward approach to their synthesis is the catalytic aziridination2 of aldimines with diazo compounds.3 During the last 20 years, this transformation has been performed with catalysts that involve an intermediate carbene complex (Scheme 1a) or, alternatively, Lewis (or Brønsted) acid activation of the imine (Scheme 1b or 1b′). In 1995, Jacobsen reported copper bisoxazoline catalysts that operate by nucleophilic attack of the imine onto a carbene

Scheme 2

Scheme 1

Received: July 25, 2013 Published: August 14, 2013 © 2013 American Chemical Society

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dx.doi.org/10.1021/om400735p | Organometallics 2013, 32, 4690−4701

Organometallics

Article

and with rhodium(II) catalysts6 and has contributed to the reputation of transition metal-catalyzed imine aziridination as a reaction of intrinsically low enantioselectivity ever since. Other copper catalysts that possibly involve Lewis acid activation of the imine showed improved enantioselectivity, but their performance was still modest.7 A successful variation of the carbene transfer approach combines a metal catalyst for diazoester decomposition with a chiral sulfide that acts as carbene shuttle to imine via a sulfur ylide intermediate,8 but the source of the chiral information is not the metal in this case. The alternative approach in metal-catalyzed aziridination, that is, nitrene transfer to an olefin,9 has been pioneered by Evans and Jacobsen and further developed by Katsuki with the use of sulfonyl azides.10 Following seminal work with achiral systems, 11 chiral, boron-based Lewis acids have been successfully used for asymmetric imine aziridination.12 More recently, chiral Brønsted acids have been shown to induce the aza-Darzens reaction of imines and diazoalkanes with high enantioselectivity.13−15 In both cases, the reaction mechanism involves the nucleophilic attack of the diazoester onto the acidactivated imine (Scheme 1, pathways b and b′). Driven by the success of this approach, the mechanistic understanding of acidcatalyzed imine aziridination has been rapidly evolving. Thus, it has been recently shown that, in the VAPOL-catalyzed aziridination, the imine is activated by hydrogen bonding to a chiral Brønsted acid derived from the chiral borane.12b Our interest in carbene transfer to imines arises from previous studies of asymmetric cyclopropanation with ruthenium complexes containing chiral tetradentate PNNP ligands such as (1S,2S)-N,N′-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine, which is used throughout this paper. The five-coordinate complex [RuCl(PNNP)]PF6 (2), formed by chloride abstraction from [RuCl2(PNNP)] (1) (Scheme 3),16,17 is a highly enantioselective catalyst for the

Scheme 4

(5a) to cis-ethyl 1-benzhydryl-3-phenylaziridine-2-carboxylate (cis-6a) with good enantioselectivity (up to 84% ee).20 Maleate formation severely reduced the yield of aziridine, which was optimized by using a temperature gradient between −78 °C and room temperature. An NMR study gave strong evidence that aziridine is formed by carbene transfer to the imine from a coordinated diazoester molecule (Scheme 1c), an unprecedented mechanism that opens the way to highly enantioselective transition metal-catalyzed imine aziridination. In the present paper, we report further advances in terms of chemoand enantioselectivity and substrate scope achieved by tuning the counterion Y− of the catalyst [RuCl(OEt2)(PNNP)]Y (4Y; Y = PF6, BF4, or SbF6), give a full account of the previously communicated NMR spectroscopic studies,20 and suggest a general explanation for the reactivity of carbene and diazoester complexes with imines.

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RESULTS AND DISCUSSION Counterion Optimization and Substrate Scope. As mentioned above, the catalyst [RuCl(OEt2)(PNNP)]PF6 (4PF6) gave significant yield of cis-ethyl 1-benzhydryl-3phenylaziridine-2-carboxylate (cis-6a) only in combination with an elaborate temperature protocol.20,21 With the goal of producing aziridine in reasonable yield and high enantioselectivity under simpler experimental conditions, the catalysts [RuCl(OEt2)(PNNP)]Y (4Y) containing other low-coordinating anions Y (Y = BF4− or SbF6−) were screened with Nbenzylidene-1,1-diphenylmethanamine (5a) as standard substrate (Table 1). The dichloro complex [RuCl2(PNNP)] (1) was activated with (OEt3)Y (Y = BF4 or SbF6, 1 equiv) overnight in dichloromethane to give 4Y (Scheme 3), after which 5a and then EDA were added to the solution cooled at 0 °C. The

Scheme 3

Table 1. Asymmetric Aziridination of 5a (at 0 °C) with Precatalyst 1 Activated with (OEt3)Ya crude 6b

asymmetric, cis-selective cyclopropanation of olefins by diazoesters with the intermediacy of the carbene complex [RuCl(CHCO2Et)(PNNP)]+.18 Therefore, on the basis of the dominant mechanistic hypothesis, it was straightforward to test Ru/PNNP catalysts in imine aziridination with ethyl diazoacetate (EDA) (Scheme 4). We have recently reported a preliminary screening of the Ru/PNNP catalysts [RuCl(L)(PNNP)]PF6 (L = nil, 2; L = OH2, 3; L = Et2O, 4PF6),19 which showed that the Et2O adduct 4PF6 aziridinates N-benzylidene-1,1-diphenylmethanamine

isolated cis-6

entry

Y

EDA (equiv)

yield (%)

cis:trans

yieldc (%)

eed (%)

1 2 3 4 5 6

PF6 BF4 SbF6 PF6 BF4 SbF6

1 1 1 4 4 4

22 32 32 35 53 58

77:23 78:22 85:15 79:21 81:19 78:22

13 24 24 30 20 40

80 78 93 53e 78 67

a

Reaction conditions: EDA (0.48 mmol, 1 equiv vs 5a) was added (neat) in one portion to a CH2Cl2 solution (3 mL) containing imine 5a (0.48 mmol) and 4Y (10 mol %), prepared by activation of [RuCl2(PNNP)] (1) (0.048 mmol) with (Et3O)Y (0.048 mmol) overnight. The total reaction time was 24 h at 0 °C. bSum of cis and trans isomers, based on the imine, by 1H NMR spectroscopy. cIsolated yield. dThe absolute configuration of cis-6a was 2R,3R. eThe isolated aziridine was contaminated with variable amounts of diethyl maleate. 4691

dx.doi.org/10.1021/om400735p | Organometallics 2013, 32, 4690−4701

Organometallics

Article

reaction of 4PF6 at a constant temperature of 0 °C gave aziridine cis-6a in low isolated yield (13%) and 80% ee (entry 1). The tetrafluoroborate analogue 4BF4 gave cis-6a with higher yield (24%), but with lower enantioselectivity (78% ee, entry 2). Finally, with the hexafluoroantimonate analogue 4SbF6, cis6a was isolated with 24% yield and 93% ee (entry 3), which is, to the best of our knowledge, the highest enantioselectivity ever achieved in transition metal-catalyzed imine aziridination. Major amounts of diethyl maleate (7) were formed with all catalysts, as usually observed in imine aziridination with carbenoids.4 Furthermore, variable amounts of the transaziridine (trans-6a) were detected in the crude reaction mixture.22 This is in contrast with the previously reported preliminary experiments with 4PF6 as catalyst, in which no more than trace amounts of the trans isomer were formed in the reaction run between −78 °C and room temperature.20 However, even when trans-aziridine was clearly visible in the 1H NMR spectrum of the crude products, pure cis-6a was readily isolated after workup (mostly as a crystalline solid), as the trans isomer was eluted together with the unreacted imine 5a.23 In an attempt to improve the yield of aziridine, an excess of EDA (4 equiv) was used with catalysts 4Y (entries 4−6). Overall, lower enantioselectivity was achieved under these conditions, and large amounts of diethyl maleate (7) were formed, which hindered the purification of 6a and other selected aziridines (see Supporting Information, Table S1). Overall, the best results were obtained with catalyst 4SbF6 in combination with a stoichiometric amount of EDA. Therefore, these conditions were used to screen the substrate scope (see below). At this stage, we do not have an explanation for the anion effect, in particular on the enantioselectivity. Low-temperature 31 P and 19F NMR spectroscopic studies of the Et2O adducts [RuCl(OEt2)(PNNP)]Y (4Y, Y = PF6, BF4, or SbF6) in CD2Cl2 aimed at detecting possible cation/anion interactions showed that the dissociation of the Et2O adduct 4 into the fivecoordinate complex 2 and Et2O is the main dynamic process in solution and failed to give conclusive evidence of the cation/ anion interactions evoked by the counterion effect observed in catalysis (see Supporting Information). However, an interesting observation that will be discussed in the context of the general mechanism is that the yield of aziridine is higher with the SbF6− and BF4−counterions, which are more coordinating than PF6−.24 The substituted benzaldimines 5b−5f (Chart 1) were used to screen the scope of the reaction with complex 4SbF6 as catalyst

Table 2. Asymmetric Aziridination of Imines 5a−5f with EDA Catalyzed by 4SbF6a crude 6b

isolated cis-6

entry

imine

yield (%)

cis:trans

yieldc (%)

eed (%)

1 2 3 4 5 6

5a 5b 5c 5d 5e 5f

32 18 16 30 46 40

85:15 85:15 84:16 cis only 93:7 90:10

24 14 9 24 34 33

93 91 75 79 83 93

a

Reaction conditions: See footnote a in Table 1. bSum of cis and trans isomers, based on the imine, by 1H NMR spectroscopy. cIsolated yield of cis-aziridine. dThe absolute configuration of cis-6a was 2R,3R; those of 6b−6f were not assigned.

was not determined. Besides 5a, the catalyst 4SbF6 gives enantioselectivity higher than 90% ee with the p-chloro- and 2naphthyl-substituted imines 5b and 5f (91 and 93% ee, respectively, entries 2, 6). The 3-bromo analogue 6e is formed with a slight erosion of enantioselectivity (83% ee), but with the highest isolated yield (34%, entry 5). The bulky 4methoxycarbonyl-substituted imine 5d gave the corresponding aziridine cis-6d with lower enantioselectivity (79% ee, entry 4), whereas 4-fluoro-substitution reduced both yield and enantioselectivity (entry 3). Interestingly, all these substrates gave higher enantioselectivity than obtained with other chiral transition metal catalysts that operate by diazoalkane activation.4 Finally, we note that the 1H NMR spectra of the reaction crude of the catalytic runs reported in Tables 1 and 2 showed not more than trace amounts (